The compound 4(2'-methoxyethyl)phenol (MEP), a substituted phenethanol ether prepared in accordance with the present invention, is a known compound. It is used as an intermediate in the production of 1-[4-(2-methoxyethyl)phenoxy]-3-[1-(1methoxyethyl)amino]-2-propanol, a beta-adrenergic blocker known as metoprolol tartrate and described in 2 Pharmaceutical Manufacturing Encyclopedia, 100-1010 (2nd ed. 1988).
Several methods have been employed in the past to manufacture 4-(2'-methoxyethyl) phenol (MEP). A method is described in Baird et al., Neighboring Carbon and Hydrogen. LI..sup.1. Dienones from Ar, O-3 Participation. Isolation and Behavior of Spiro (2,5)octa-1,4-diene-3-one, 85 Am. Chem. Soc'y 567, 575 (1963) and in Communication to the Editor from Baird et al., 79 Am. Chem. Soc'y 756-757 (1957). In that method, 4-(2'-methoxyethyl)phenol is synthesized from phenylacetic acid through a multi-step process.
French Patent 2,487,338 discloses the preparation of 4-(2'-methoxyethyl)- phenol utilizing brominated alkoxyphenol as a starting material. The method utilizes a multi-step process which includes a technically difficult Grignard reaction.
Belgian patent 885,030 discloses another method for the preparation of 4-(2'-methoxyethyl)phenol. In that method, the starting material is 4-hydroxystyrene. Several steps are used to obtain the final product.
Still another method for the production of 4-(2'-methoxyethyl)phenol is disclosed in Hallberg et al., A New Route to 4-(2'-methoxyethyl)phenol via Palladium-Catalyzed Arylation of Methyl Vinyl Ether, 15(13) Synthetic Com., 1131-6 (1985) wherein 4-(2'-methoxyethyl)phenol is prepared via palladium-catalyzed arylation of methyl vinyl ether. The palladium catalyzed reaction of methyl vinyl ether with 4-bromonitrobenzene, followed by hydrogenation and subsequent diazotization forms 4-(2'-methoxyethyl)phenol.
In U.S. Pat. No. 5,107,034, there is described a process for preparing MEP by brominating 4-hydroxyacetophenone to produce alpha-bromo-5-hydroxy-acetophenone, and then causing a methoxide-bromide exchange to thereby produce alpha-methoxy-4-hydroxyacetophenone; and then conducting a single step reduction of alpha-methoxy-4-hydroxyacetophenone with at least two (2) equivalents of hydrogen per equivalent of alpha-methoxy-4-hydroxyacetophenone in the presence of a hydrogenation catalyst to thereby directly produce MEP.
In U.S. Pat. No. 5,124,489, there is disclosed a process for preparing substituted phenethanol ethers by the catalytic reduction of corresponding substituted phenylglyoxal acetals.
The above prior art references are disclosed in accordance with the terms of 37 CFR 1.56, 1.97, and 1.98. All of these references are incorporated herein by reference in their entirety.
One of the disadvantages of the above-referenced processes is that they include several, often complex, steps which give rise to economical and ecological problems. Furthermore, another disadvantage of some of the above-referenced processes is that they utilize expensive starting materials.
According to the present invention, a simple economical method is disclosed wherein 4-hydroxyphenethyl alcohol, a commercially available material, is subjected to etherification to prepare 4-(2'-methoxyethyl)phenol (MEP). The method is also employed to prepare other substituted phenethanol ethers which are believed to be useful as intermediates in pharmaceutical products by the etherification of corresponding substituted phenethyl alcohols.
These and other advantages and objects of the present invention will become apparent from the following description.